The invention relates to immuno privileged cells and the use thereof in tissue transplant and cell-based therapies.
Insulin dependent diabetes mellitus (IDDM) in humans and in non-obese diabetic (NOD) mice is an immune-mediated disorder in which mononuclear cells invade the pancreatic islets of Langerhans (insulitis) and effect the selective destruction of insulin-secreting pancreatic β cells (Eisenbarth G. S. (1983) N. Engl. J. Med. 308, 322–27). Since the introduction of insulin therapy in 1922, the majority of acute deaths due to insulin deficiency have been prevented. However, current insulin treatment regimens are still suboptimal for blood glucose control and patients with IDDM are at significant risk for the development of serious long-term complications such as blindness and kidney disease. Although progress is being made in the field of allogeneic islet transplantation as an alternative approach to the treatment of IDDM, the clinical applicability of this approach has been severely limited by the scarce supply of available islets and the rapid and aggressive recurrence of autoimmune disease in transplanted islet grafts, which occurs despite treatment with systemic immunotherapy (Tyden et al., NEJM, 1996).
Hepatocytes and the anterior pituitary tumor cell line, AtT20, have been studied as potential insulin producing cells. Proinsulin, when transfected into hepatocytes, which have only a constitutive pathway of protein secretion is processed to insulin extremely inefficiently (Valera, A., Fillat, C., Costa, C., Sabater, J., Visa, J., Paujol, A. & Bosch, F. (1994) FASEB J. 8, 440–447; Kolodka, T. M., Finegold M., Moss L, Woo S. L. C. (1995) Proc. Natl. Acad. Sci. USA 92 3293–3297). AtT20 cells have a regulated secretory pathway, with characteristic secretory granules containing the prohormone endopeptidases PC2 (Smeekens, S. P., Avruch, A. S., LaMendola, J., Chan, S. J. & Steiner, D. F. (1991) Proc. Natl. Acad. Sci. USA 88, 340–344), PC1/PC3 (Seidah, N. G., Marcinkiewicz, M. & Benjannet, S. (1991) Mol. Endocrinol. 5, 111–122), and carboxypeptidase H (Davidson, H. W. & Hutton, J. C. (1987) Biochem. J. 245, 575–582) that normally convert the prohormone proopiomelanocortin (POMC) to ACTH and other peptides. Proinsulin, when transfected into AtT20 cells, is processed to mature insulin, identical in structure to native (i.e., β-cell derived) insulin (Moore, H.-P., Walker, M. D., Lee, F., & Kelly R. B. (1983) Cell 35, 531–538; Ferber, S. Gross, D. J., Villa-Komaroff, L., Vollenweider, F., Meyer, K., Loeken, M., Kahn, C. R. & Halban, P. A. (1991) Mol. Endo. 5, 319–326). A major limitation of using transfected anterior pituitary cells for insulin gene delivery is that their major endogenous secretory product is ACTH, and, thus, implantation of these cells into diabetic recipients can result in a severe Cushings-like hypercortisolemic syndrome (BeltrandelRio, H., Schnedl, W. J., Ferber, S. & Newgard C. B. in Pancreatic Islet Transplantation, Vol 1, Lanza, R. P and Chick, W. L., Ed., R. G. Landes Company, Austin, pp 169–178, 1994). In addition, AtT20 cells, like many transformed β-cell lines, have an active constitutive pathway, with proinsulin comprising up to 25% of the secreted immunoreactive insulin (Gross, D. J., Halban, P. A., Kahn, C. P. Weir, G. C., Villa-Komaroff, L. (1989) Proc. Natl. Acad. Sci. USA 86, 4107–4111).